Composition for use in the prevention and/or treatment of oncologic treatment induced orogastrointestinal mucositis

ABSTRACT

The present invention refers to a composition for use in the prevention and/or treatment of orogastrointestinal mucositis induced by oncologic treatments. It also refers to the use of said composition for preparing a medicament for the prevention and/or treatment of said orogastrointestinal mucositis. Furthermore, it refers to a method of preventing and/or treating of said orogastrointestinal mucositis in which said composition is administered to a subject in need thereof.

FIELD OF THE INVENTION

The present invention refers to the field of cancer therapy and itssecondary effects, in particular it refers to a composition for use inthe prevention and/or treatment of Oncologic Treatment InducedOrogastrointestinal Mucositis.

BACKGROUND OF THE INVENTION

Oncologic Treatment Induced Orogastrointestinal Mucositis is a cancertherapy-toxicity related mucosal injury of the alimentary tract that isrecognized as a serious and debilitating side effect of cancer therapy.The mucosa of the respiratory tract is also a target for this toxicity.Thus, in the present invention, Oncologic Treatment InducedOrogastrointestinal Mucositis (abbreviated and referred to as OTIOM) isa mucosal injury of the aerodigestive tract, which comprises thealimentary tract and the respiratory tract, induced by cancer therapy.

Synonymous of OTIOM are “Orogastrointestinal Oncologic Mucositis”,“Oncologic Mucositis”, “Gastrointestinal Mucositis”, also historicallycalled “Oral Mucositis”, abbreviated by some authors to “Mucositis”, thelatter leading to confusion with the non-malignant, non-life threateninglocal saliva-impairment related stomatitis or mucositis (see below).

OTIOM is currently the single most severe and more feared complicationof cancer therapy. It often leads to unplanned treatment interruptionsand chemotherapy dose reductions which reduce the loco-regional tumorcontrol while allowing tumor repopulation which may lead to re-growth ofchemotherapy-resistant cell population. Its morbidity is no longerunderestimated leading to potentially a decrease in cancer survivalrate, sepsis, and even fatal outcome during the cancer treatment.

All the ducts, cavities and organs that form the aerodigestive tractshare a common feature, the mucosa barrier. OTIOM is primarilycharacterized by damage of not only the epithelium, as was historicallythought, but the totality of the mucosa and the subjacent connectivetissue.

OTIOM typically courses with mouth ulcers, pain that can make nutritionintolerable, vomiting, diarrhea, rectal bleeding and abdominal cramps,to name a few. It is autolimitating, but upon appearance leaves thepatient prone to more episodes. Even though it preferably appears in thealimentary tract, proctitis following radiation is also considered amanifestation of OTIOM. Mucosal injury related to cancer therapy canoccur in other mucosal barriers throughout the body, like vagina andeven bronchi and lungs between others.

The incidence of OTIOM reaches 51% of all chemotherapy for solid tumorsor lymphoma. In patients with high dosage chemotherapy before stem cellor hematopoietic cell transplantation this percentage rises to 75-80%.Patients treated for head and neck cancer develop OTIOM almost in 100%of cases, 29-66% of them in the severe form. In patients withradiotherapy for oral cancer, OTIOM will appear in 90-100% of the cases.

OTIOM is therefore a serious complication characterized by the onset ofa disruption or breakage of the aerodigestive mucosa. At the initialstage it can happen as erythema or redness of the mucosa, withpseudomembranous lesions more or less extended that gradually mergeuntil the mucosa is ulcerated throughout its depth. At this stageprofuse bleeding with significant pain impair normal digestive tractfunction.

At the initial stages OTIOM usually appears as lesions in the mucosa ofthe oral cavity, classically originating the diagnosis of oralmucositis. The same type of lesions can simultaneously occur along thewhole digestive tract. However, difficulty in diagnosis of the initiallesions of the mucosa in the internal organs of the digestive tract isdelayed until more severe breakage of the mucosa barrier progresses tointolerable diarrhea with even visible bleeding through the anus.

In 1969, oral involvement of one of the most common diseases of theintestine, that is Crohn's disease, was described. More recently, Dupuyet al (Oral Crohn disease: clinical characteristics and long-termfollow-up of 9 cases. Arch Dermatol 1999; 135:439-442.) explained thatmany diseases of the digestive tract were easier to diagnose in the oralcavity that in the intestine because it is easily examined directly. Inthe same manner, Oral Mucositis is the expression in the oral cavity ofOTIOM while Gastrointestinal Mucositis in the digestive tract, but bothare the same clinical conditions.

One of the biggest difficulties regarding OTIOM resides in being able todescribe precisely, objectively and in a reproducible way the severityof mucosal damage. Unfortunately regardless of a number of assessmentscales available today there is still need for the definitive scaleaccepted universally for producing systematic validated data.

In the original publication from World Health Organisation (WHO,Handbook For Reporting Results Of Cancer Treatment. Geneva: WHO OffsetPublication, 1979) a recommendation for grading the toxic effects ofcancer therapy is found. WHO puts together a wide variety of signs andsymptoms and grades them from 0 to 4 (see Table 1 of WHO OffsetPublication 1979, of which the gastrointestinal part is extracted inTable 1 below).

TABLE 1 Recommendations for grading of acute and subacute toxiceffects - Gastrointestinal 0 1 2 3 4 Bilirubin ≤1.25 × N^(a) 1.26-2.5 ×N^(a) 2.6-5 × N^(a) 5.1-10 × N^(a) >10 × N^(a) Transaminases ≤1.25 ×N^(a) 1.26-2.5 × N^(a) 2.6-5 × N^(a) 5.1-10 × N^(a) >10 × N^(a)(SGOT/SGPT) Alkaline ≤1.25 × N^(a) 1.26-2.5 × N^(a) 2.6-5 × N^(a) 5.1-10× N^(a) >10 × N^(a) phosphatase Oral No change Soreness/ Erythema,Ulcers; requires Alimentation not erythema ulcers; can eat liquid dietonly possible solids Nausea/ None Nausea Transient Vomiting IntractableVomiting vomiting requiring therapy vomiting Diarrhoea None Transient, <Tolerable, but > Intolerable, Haemorrhagic 2 d 2 d requires therapydehydration N^(a) = upper limit of normal value of population understudy.

This publication has inspired many others and one example is seen inTable 2, which outlines the main two of the multiple orogastrointestinalevents that unfortunately may happen in a subject affected by OTIOM:Oral mucositis and diarrhea.

TABLE 2 WHO grading scale of oral mucositis and diarrhea (Koning et al,2007, Chemotherapy Does Not Influence Intestinal Amino Acid Uptake inChildren. Pediatric Research 62; 1995-199). Grade Oral mucositisDiarrhea 0 None None 1 Oral soreness, erythema and pain Transient, <2 d2 Oral erythema, ulcers, can eat solids Tolerable, but >2 d 3 Oralulcers, requires liquid diet only Intolerable, requires therapy 4 Oralalimentation not possible, nutrition by Haemorrhagic dehydration tube ortotal parenteral mandatory

Grades 3 and 4 are considered to be severe oral mucositis, and in thecontext of the present invention, are also considered as severe OTIOM.

More recently, regarding the relation of the origin of the toxicity onthe severity of the presentation of the OTIOM it is usually acceptedthat radiotherapy with concomitant chemotherapy augments the severity ofthe lesions. New fractioned radiotherapy may have better local controlbut with more acute severe oral mucositis (rapid onset of the lesions).More recently, conformational radiotherapy with IMRT seems to reduce therisk of acute oral mucositis grade 3. Nonetheless all attempts to avoidpresentation of OTIOM seem to be unsuccessful up until today.

Severe forms of OTIOM can require hospitalization, need for narcoticanalgesics, can lead to suboptimal delivery of antineoplasic treatments,parenteral nutrition and are related with morbidity and mortality fromsepsis, dehydration or other complications.

Current management of OTIOM is still managed only symptomatically,mostly by oncologists and onco-nurses. Most of the cases are seen inhospitals and require many times hospitalization. These patients are notseen neither followed by the dentist, whom instead does seemoisture-deprived stomatitis or mucositis in cases of hyposalivation.

The management of OTIOM consists primarily in elimination or reductionof pain. Providing nutritional support through prevention of dehydrationor providing rehydratation and prevention of malnutrition together withoral hygiene measures whenever possible and prevention of infectionsand/or sepsis, and handling digestive tract bleeding are the mostimportant approaches during the acute episode. Lalla et al. (2014,MASCC/ISOO clinical practice guidelines for the management of mucositissecondary to cancer therapy. Cancer, 120 (10), 1453-1461) describe theclinical practice guidelines for the management of OTIOM (referredtherein as mucositis secondary to cancer therapy). Said guidelinesdescribe drugs such as lidocaine, fentanile, opiods and morphine thatare used to control pain; do not recommend the use of chlorhexidinemouthwashes for the treatment of OTIOM, especially in the presence ofulceration; and do not recommend the use of antibiotics or acyclovir toprevent OTIOM on a routinely basis.

Apart from the symptomatic control described above, there is no cleartherapeutic agreement, given the lack of clinical evidence in theliterature, supporting any successful approach to either prevent ortreat OTIOM.

Therefore, there is still a need in the state of the art of providingcompositions for use in the prevention and/or treatment of OTIOM.Surprisingly, the authors of the present invention have developed acomposition for such use.

OBJECT OF THE INVENTION

A first aspect of the present invention refers to a compositioncomprising olive oil, trimethylglycine and xylitol for use in theprevention and/or treatment of OTIOM.

A second aspect of the present invention refers to the use of acomposition comprising olive oil, trimethylglycine and xylitol for thepreparation of a medicament for the prevention and/or treatment ofOTIOM.

A third aspect of the present invention refers to a method of treatingOTIOM in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a composition comprisingolive oil, trimethylglycine and xylitol.

A fourth aspect of the present invention refers to a method ofpreventing OTIOM in a subject which comprises administering to thesubject a prophylactically effective amount of a composition comprisingolive oil, trimethylglycine and xylitol.

A fifth aspect of the present invention refers to a compositioncomprising:

olive oil,

trimethylglycine,

xylitol, and

hydroxytyrosol and/or tyrosol and/or oleuropein.

Other objects, features, advantages and aspects of the presentapplication will become apparent to those skilled in the art from thefollowing description and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the singular forms “a,” “an” and “the” include theircorresponding plural forms unless the context clearly indicatesotherwise. Unless defined otherwise, all the technical and scientificterms used herein have the same meaning as commonly understood by aperson skilled in the art to which this invention belongs. To facilitateunderstanding and clarify the meaning of specific terms in the contextof the present invention, the following definitions and particular andpreferred embodiments thereof, applicable to all the embodiments of thedifferent aspects of the present invention, are provided:

OTIOM refers to orogastrointestinal mucositis induced by a cancertherapy. As explained above, OTIOM is a mucosal injury of theaerodigestive tract, which comprises the alimentary tract and therespiratory tract, induced by cancer therapy. Thus, in a particularembodiment, OTIOM affects the alimentary tract and/or respiratory tract.In another particular embodiment, OTIOM affects one or more partsselected from the group consisting of oral cavity, tongue, lips,pharynx, esophagus, stomach, intestine, rectum, anus, nose, nasal tract,paranasal sinuses, throat, vocal cords, and larynx. More particularly,OTIOM affects the oral cavity, lips, tongue, esophagus, stomach,intestine, rectum, anus and combinations therefore, more preferably, theoral cavity. In another particular embodiment, the oncologic treatmentthat induces orogastrointestinal mucositis is selected from the groupconsisting of chemotherapy, radiotherapy, immunotherapy, hormonaltherapy, stem cell transplantation and combinations thereof. These termsare well known by the skilled in the art. Preferably, the oncologictreatment is chemotherapy and/or radiotherapy.

As mentioned in the background section, some authors classified OTIOMgrades according to WHO's recommendations for grading of acute andsubacute toxic effects of cancer therapy. Konrad classified the gradesof the main affections of OTIOM: oral mucositis and diahrrea (see Table2, above). Thus, in the present invention, the grading shown in Table 2is considered to be the grading of OTIOM, and grades 3 and 4 areconsidered as severe OTIOM.

OTIOM should not be confused with the so called periimplantitis orperi-implant mucositis commonly discussed in the field of implantdentistry, a chronic affection of the support bone surrounding dentalimplants that has in the loss of the implant the most notoriousconsequence and that is often asymptomatic.

Likewise, OTIOM should not be confused with dysphagia and xerostomia,which happen in the oral environment. A number of conditions might bethe origin of dysphagia and xerostomia in patients with cancer. Surgeryand radiation of the head and neck are a clear cause for these twochronic oral complications, but neurological disorders, age,degenerative conditions, Sjögren syndrome, diabetes, and polymedicationbetween others are also common diagnoses that explain these two symptomsand do not necessarily imply that the patient has cancer.

Dysphagia is a debilitating, depressing, and potentiallylife-threatening complication in cancer patients that is likelyunderreported and described as a swallowing disturbance due essentiallyto muscular conditions. Dysphagia is related to a number of factors suchas direct impact of the tumor, cancer resection, chemotherapy, andradiotherapy and to newer therapies such as epidermal growth factorreceptor inhibitors.

Xerostomia, also called dry mouth syndrome and burning mouth, isdiagnosed when the amount or quality of saliva diminishes(hyposalivation). The prevalence of xerostomia is 22-26% in the generalpopulation, and 50-55% in mixed oncology populations. It has an originin an alteration of the salivary gland normal function with a change inthe histology of the gland parenchyma and acini. The etiology is usuallypolypharmacy or intake of mouth-drying drugs. Furthermore in head andneck cancer patients, xerostomia is a highly common complication ofradiotherapy due to the irreversible damage to the salivary glands,remaining as a chronic collateral effect in a 93% of this group ofpatients. Surgery can also originate dry mouth syndrome. Thus,xerostomia is one of the most common complications experienced by allgroups of oncology patients. However, perception of this somewhatchronical, low profile syndrome, is unimportant for many oncotherapistsand patients, viewing other symptoms more important. Xerostomia affectssignificantly quality of life but is never a challenge for the patientsurvival. Many patients tolerate a diminished or poor salivary functionand learn to live with it. In fact, 50% of xerostomia patients do notshow any symptoms, and what is scientifically more relevant up to 50% ofsalivary flow may be lost before xerostomia manifests itself with signsor symptoms without yet perceiving dryness in the mouth.

Xerostomia can cause many chronic faringitis and a cohort of signs andsymptoms labeled as stomatitis or mucositis (unspecificstomatitis-mucositis), the latter a non-malignant, non-life threateninglocal saliva-impairement manifestation of lack of moisture with a cohortof signs and symptoms like tongue fissures, dysgeusia (lack or alteredtaste), oral soreness, inability to wear dentures, affecting purely themouth generally with a chronic course. Oral mucosa appears intact with adull or anodyne redness, flatness or smoothness of the oral mucosa andtongue or in the contrary with increased rugosities and villis from thetongue also named “glositis”, with or without white furry tongue.

Due to the sustained lack of lubricant, roughness causes oralirritation, especially in locations in contact with poorly fitting,inadequate or aged prosthesis. In this situation a candidiasis orinfection by candida may superimpose. This so called candida mucositisor candida stomatitis is successfully treated with antifungical drugsand is in most cases asymptomatic.

All these clinical scenarios of unspecific stomatitis-mucositis arelocal, non-malignant, and never a challenge to the patient's life. Theyare diagnosed and treated by the dentist at the dental office throughstimulating the salivary flow and/or polishing existing worn-outroughened restorations or via delivery of new prosthesis or restorationswith highly polished materials and adequate designs.

Xerostomia and this xerostomia related stomatitis-mucositis, havegenerally a chronic course, and no matter how persistent they are, theywill not lead to the onset of OTIOM, nor to diarrhea, nor vomits, noranal bleeding nor ulceration of the alimentary canal neither the airway.They do not require hospitalization, or parenteral nutrition, orintravenous opioids, or advanced medical support, or in any case arethey related to mortality.

“Prevention” refers to the absence of severe OTIOM, i.e. absence ofOTIOM in the grades of 3 and 4. Thus, with the prevention of the presentinvention the subject will not have oral ulcers which make him requireliquid diet only or impede oral alimentation completely (i.e. forcesnutrition by tube or parenteral nutrition only). Moreover, the subjectwill not have intolerable diarrhea that requires therapy or rehydration.Moreover, the prevention refers to a reduction of the appearance of mildand moderate OTIOM (grades 1 and 2, or grade 2), compared to subjectsnot using the composition of the invention (see Example 1).

“Prophylactically effective amount” refers to an amount that iseffective to eliminate the symptoms of severe OTIOM.

“Treatment” refers to the reduction of the symptoms and/or reduction ofthe duration of the symptoms of all grades of OTIOM. Preferably, itrefers to the reduction of the symptoms and of the duration time ofOTIOM.

“Therapeutically effective amount” refers to an amount that is effectiveto reduce the symptoms and/or duration of the symptoms of all grades ofOTIOM.

In a first aspect, the present invention refers to a compositioncomprising olive oil, trimethylglycine (TMG) and xylitol (hereinafterreferred to as composition of the invention) for use in the preventionand/or treatment of OTIOM.

Compositions comprising olive oil, TMG and xylitol are already known inthe state of the art, see for example U.S. Pat. No. 8,540,970 B2. Inparticular, U.S. Pat. No. 8,540,970′s composition can be used for thetreatment of xerostomia. However, as mentioned above, xerostomia andxerostomia-induced stomatitis-mucositis are conditions completelydifferent to OTIOM, and xerostomia does not lead to the onset of OTIOM.Moreover, the risk factors for the development of OTIOM may becategorized as tumor-related, treatment-related, and patient-related,among them a possible genetic predisposition. Xerostomia does not appearin any of these categories (Epstein et al., 2012, Cancer, “OralComplications of Cancer and Cancer Therapy”).

Furthermore, nothing in the state of the art suggests that a propersalivary function would prevent OTIOM from occurring, nor that patientswith a maintained salivary flow would be OTIOM-risk free. In fact,patients with OTIOM do not tolerate any stimuli in the mouth and the useof saliva stimulants with its best representative, pilocarpine, hasshown no beneficial effect in preventing or treating OTIOM (Lelia, etal., 2014).

Thus, an expert in the field, in view of the general malaise of thesepatients, especially with OTIOM of grade 3 or 4, and the overallintolerance not only to solids but also to liquids (to the point thatthey have to remove saliva from their mouths with a gauze in order notto swallow), would have been motivated not to recommend salivarystimulation for this type of patients.

Thus, even when compositions comprising olive oil, TMG and xylitol havealready been described, in particular for use in the treatment ofxerostomia, the skilled in the art would not have been motivated to usesuch composition for the prevention and/or treatment of OTIOM.

In relation to the different components of the composition of theinvention, none of them has been individually linked with the preventionand/or treatment of OTIOM as defined in the present invention. Olive oilis the main ingredient of the well documented and internationallyrespected Mediterranean diet. Would olive oil “per se” be effective toprevent OTIOM, given the widespread and significant intake of olive oilin Mediterranean countries, the prevalence of OTIOM would be less commonor non-existing in this geographical area. However, this is not thecase, even when fairly conclusively data have demonstrated that peoplethat live in the Mediterranean countries and follow the Mediterraneandiet enjoy health benefits, namely in cardiovascular, degenerative butalso enjoy cancer benefits especially lower breast and colon cancerfigures.

Moreover, it has been shown that in oral mucositis grade 3 there were nosignificant differences between the use of honey alone or the use ofhoney mixed with the olive oil-propolis extract and beeswax, while inmucositis grade 2 the efficacy in reducing recovery time proven forhoney alone, was reduced when honey was mixed with the oliveoil-propolis extract and beeswax (Abdulrhman et al., PediatricHematology and Oncology (2012) 29, 285-292., “Honey and a Mixture ofHoney, Beeswax, and Olive Oil-Propolis Extract in Treatment ofChemotherapy-Induced Oral Mucositis: A Randomized Controlled PilotStudy”). Thus, olive oil does not seem to be beneficial in the treatmentof chemotherapy-induced oral mucositis.

Xylitol, has proven to be effective fighting caries as it is nonfermentable by most oral bacteria. It has also been proved that it doesnot change the digestive microflora. No evidence supports the relationof xylitol with the immediate wellbeing and relief that patients withOTIOM obtain with the administration of the composition of the presentinvention.

TMG has been related in the patent U.S. Pat. No. 6,156,293 with theimprovement of skin and skull dryness, but not with improvement ofcancer therapy related mucosal injury or of ulceration of theorogastrointestinal mucosa.

Surprisingly, the composition of the present invention, comprising oliveoil, TMG and xylitol, is useful for the prevention and/or treatment ofOTIOM.

TMG has osmoprotective action and has no surfactant action. It shouldnot be confused with the cocamidopropyl betaine (CAPB), being this one adetergent with surfactant action commonly used in oral hygiene products.In the composition of the present invention all detergents are excluded,specially taking into consideration that the group of patientsencompasses a challenge to the mucosal integrity and detergents aretotally deleterious in such case. Thus, in a particular embodiment, thecomposition of the present invention, according to any one of theembodiment of the present invention, does not comprise any detergent.Thus, the composition of the invention does not comprise sodium laurylsulphate, sodium lauryl sarcosinate, CAPB, or detergents commonly usedin oral hygiene products, preferably it does not comprise sodium laurylsulphate, sodium lauryl sarcosinate or CAPB. Likewise, in a preferredembodiment according to any one of the previous embodiments, thecomposition of the invention does not comprise alcohol, since alcoholmay dry out the mouth and increase pain.

In a particular embodiment according to any one of the previousembodiments, the composition of the invention comprises 0.1%-5% byweight of olive oil, preferably 0.2%-4% by weight of olive oil, and morepreferably 0.2%-2.5% by weight of olive oil. As shown in the Examples,compositions comprising an amount of olive oil within these ranges arevery effective in the prevention and treatment of OTIOM.

All the percentages given in the present invention, are given in weightby weight of the total composition (w/w), unless otherwise stated.

In a particular embodiment according to any one of the previousembodiments, the composition of the invention comprises 0.1%-10% byweight of TMG, preferably 1.5%-6% and more preferably 2%-4% by weight.

In a particular embodiment according to any one of the previousembodiments, the composition of the invention comprises 1%-50% by weightof xylitol, preferably 1%-30% and more preferably 1-15%, and even morepreferably 10%.

In a preferred embodiment, the composition of the invention comprises0.2%-4% by weight of olive oil, 1.5%-6% by weight of TMG and 1%-30% byweight of xylitol.

In another preferred embodiment, the composition of the inventioncomprises 0.2%-2.5% by weight of olive oil, 2%-4% by weight of TMG and1%-15% by weight of xylitol.

As shown in the Examples, compositions comprising an amount of oliveoil, TMG and xylitol within the ranges defined above are very effectivein the prevention and treatment of OTIOM.

In another preferred embodiment, the composition of the inventioncomprises olive oil, TMG and xylitol in the amounts defined in any oneof the formulations described in the Examples (formulations 1-6).

In a particular embodiment according to any one of the previousembodiments, olive oil is extra virgin olive oil. In another particularembodiment, the composition does not comprise any other vegetable oil,except essential oils. Like this, the use of oils of lower quality, e.g.palma oil, is avoided, since the use of these oils has been recentlylinked with highly significant increase and size of the metastasis ofhuman oral carcinoma.

In a particular embodiment according to any one of the precedingembodiments, the composition comprises an antioxidant, preferably anatural antioxidant. Particularly, the antioxidant is selected from thegroup of tocopherol acetate, vitamin C, hydroxytyrosol, tyrosol,oleuropein, and mixtures thereof.

Interestingly, hydroxytyrosol, tyrosol and oleuropein potentiate theanti-inflammatory, anti-bacterial and anti-oxidant activities of theolive oil, and appear to be able to stabilize the composition (i.e.reducing, or even eliminating, the need of further preservatives whichwill make the formulation more tolerable by the subjects, particularlyif they suffer severe OTIOM). Thus, in a preferred embodiment thecomposition comprises hydroxytyrosol and/or tyrosol and/or oleuropein,preferably it comprises hydroxytyrosol, tyrosol and oleuropein. Thesethree antioxidants can be provided using olive fruit extract.

Examples of composition comprising these antioxidants are theformulation 5 and 6 of the present invention, which are thereforepreferred.

In another particular embodiment according to any of the embodimentspreviously described, the composition does not comprise a source offluorine. Like this, it can be swallowed, i.e. reaching other parts ofthe digestive tract apart from the oral cavity, without anycontraindication for the subject. Examples of formulation not comprisingfluorine sources are the formulation 5 and 6 of the present invention,which are therefore preferred, especially for the treatment of OTIOM, inparticular OTIOM of grade 3 and 4

In another particular embodiment according to any one of the previousembodiments, the composition of the invention further comprises one ormore components selected from the group consisting of remineralisingagents, viscosity-controlling agents, moisturising agents,preservatives, colorants, pH-regulating agents, sweeteners, proteolyticenzymes, emulsifiers, abrasives, essential oils, cicatrizing agents,aromas, antioxidants, animal or plant gelatines, excipients, and amixture thereof.

Preferably, the composition of the invention according to any one of theprevious embodiments, comprises a cicatrizing, an antioxidant, a buffer,a preservative, a moisturizing and a solvent (preferably water); andoptionally a rheological agent and/or an emulsifier. In a particularembodiment according to any one of the embodiments disclosed in thepresent paragraph, the composition comprises a sweetener, a colorant, anaroma, an essential oil, an abrasive, a proteolytic enzyme, aremineralising or combinations thereof.

In another preferred embodiment according to any of the precedingembodiments, the composition of the invention does not comprise eitheraroma or essential oil. This embodiment is specially preferred in casesof treatment of OTIOM, preferably severe OTIOM, to facilitate toleranceby the patient.

In another preferred embodiment according to any of the precedingembodiments, the composition of the invention does not comprise eitherof abrasive agent, fluorine source or proteolytic enzyme. Thisembodiment is specially preferred in cases of treatment of OTIOM,preferably of severe OTIOM, to facilitate tolerance by the patient.

Thus, in a more preferred embodiment according to any of the precedingembodiments, the composition of the present invention does not compriseeither of aroma, essential oil, abrasive agent, fluorine source orproteolytic enzyme. This composition is preferably used for thetreatment of OTIOM, preferably of severe OTIOM.

These further components of the composition of the invention arecommonly known by the skilled in the art, and non-limiting examples ofsaid compounds are given below. In a particular embodiment according toany one of the preceding embodiments, these compounds are selected fromthe examples given below.

The remineralising agents provide ions that allow remineralisation,specifically fluorine from any appropriate source (fluorine source),calcium from any appropriate source, as well as phosphates or other ionswith remineralising capacity and capable of hardening the teeth. Theremineralising agent can be selected from the group consisting offluoride anions, phosphate anions, calcium cations, sodium cations,potassium cations and mixtures thereof. Among the aforementioned thefollowing are cited as examples: potassium fluoride, sodium fluoride,sodium monofluorophosphate, tin fluoride, amine fluorides(hexadecylamine hydrofluoride,bis-(hydroxyethyl)aminopropyl-Nhydroxyethyl-octadecylaminedihydrofluoride, N-N′,N′-tri (polyoxyethylene)-N-hexadecyl-propylenediamine dihydrofluoride or octadecenylamine hydrofluoride),potassium phosphate, potassium pyrophosphate, tripotassium citrate,calcium lactate, calcium pantothenate and calcium carbonate. Potassiumfluoride, sodium fluoride, sodium monofluorophosphate, tin fluoride,amine fluorides are fluorine sources. Thus, in those embodiments inwhich the composition does not comprise fluorine source but comprise aremineralising agent, the remineralising agent will not be a fluorinesource.

Any rheologic agent known in the state of the art can be used asviscosity-controlling agents. In particular, the rheologic agent can beselected from the group consisting of gum arabic, tragacanth gum,xanthan gum, carboxymethyl cellulose (CMC), carbopol-type polymers,pectins, mucines and mixtures thereof.

Any moisturising agent known in the state of the art can be used in thecomposition of the invention. In particular, the moisturising agent canbe selected from the group consisting of glycerine, propylene glycol,sorbitol and mixtures thereof, preferably glycerine.

Among the preservatives that can be used in the composition of theinvention, sodium benzoate, benzoic acid, potassium sorbate,diazolidinyl urea, imidazolinyl urea, sodium methylparaben, sodiumpropylparaben, and mixtures thereof are preferred.

Any colorant of the state of the art can be used in the composition ofthe invention. In particular, the colorant can be selected from thegroup consisting of C.I. 75810, titanium dioxide and mixtures thereof.

In the composition of the invention any pH-regulating agent (alsoreferred to as buffer) known in the state of the art can be used. Inparticular, the pH-regulating agent can be selected from the groupconsisting of lactic acid, lactates, citric acid, citrates, malic acidand salts thereof, sodium hydroxide, potassium phosphates, sodiumphosphates, potassium pyrophosphate, sodium pyrophosphates and mixturesthereof.

Any sweetener known in the state of the art can be used in thecomposition of the invention. In particular, the sweetener can beselected from the group consisting of maltitol, isomaltitol, manitol,lactitol, sodium saccharine, acesulfame potassium, aspartame, cyclamate,taumatin, sucralose, estevia rebaudiana, neohesperidine DC and mixturesthereof.

Proteolytic enzymes such as papain, for example, can also beincorporated to the composition of the invention. This can be usefulwhen mucosal injury lesions are present since it facilitates cleaning ofthe debris and reduces the dead cells that have been accounted forspurring the disruption of the mucosa.

Any suitable emulsifier known in the art can be used in the compositionof the invention. In particular, the emulsifier can be selected from thegroup consisting of polyethylene glycol (PEG) 40 hydrogenated castoroil, lecithin and mixtures thereof.

A mild abrasive agent can also be used in the composition of theinvention, preferably low abrasion silica, in particular, selected fromthe group consisting of hydrated silicas (such as Syloid 244, Zeodent163, Zeodent 623).

As mentioned above, the composition of the invention can incorporateessential oils such as parsley seed oil and/or citrus medica oil.

Any cicatrizing agent known in the state of the art can be used in thecomposition of the invention, in particular, selected from the groupconsisting of allantoin, D-panthenol, calcium pantothenate, and mixturesthereof.

The composition of the invention can comprise animal and/or plantgelatine such as bovine gelatine, fish gelatine, algae gelatine, andmixtures thereof.

The composition of the invention can also include aromas such as citrusmedica or mint extracts, for example.

Finally, suitable excipients will be added to the composition of theinvention according to the formulation they are intended for. Thus,beeswax, gum base, carnauba wax or shellac, etc can be used.

In another particular embodiment according to any of the previousembodiments, the composition of the invention does not comprise anyadditional active principle. In particular, it does not comprisepilocarpine, pentoxifylline, cyclosporine,granulocyte-macrophage-colony-stimulating factor, anti-interleukin-6antibody, acyclovir, antimicrobial agents, chlorhexidine, mesalazine,olsalazine, sucralfate, 5-acetyl salicylic acid, misoprostol, orcombinations thereof. More particularly, it does not comprise honeyand/or propolis.

According to the desired presentation/formulation, the composition caninclude all those components necessary to provide the desiredorganoleptic and rheologic form.

Preferably, the composition of the invention has a neutral pH (between 6and 7.5). Moreover, in the case of liquid and doughy preparations, wateris used as a solvent.

During the treatment of the OTIOM an aqueous solution is preferred andthe need for an emulsifier is reduced. Thus, in a preferred embodimentaccording to any one of the embodiment of the first aspect of theinvention, the composition is an aqueous solution and it does notcomprise an emulsifier.

In a particular embodiment, the composition of the invention isformulated as solution (e.g. mouthwash), spray, gel, syrup, toothpaste,chewing gum, suckable capsules, suckable lozenges, palate sheets,tablets, sweets, impregnated oral swabs, impregnated oral gauzes,sucking tablets, topical solutions, topical ointments with or withoutapplicators.

The solution, spray, gel and syrup are considered in the presentinvention as liquid dosage forms. In a preferred embodiment according toany one of the previous embodiments, the composition of the invention isformulated as an aqueous liquid dosage form.

In general, as well as the swabs and gauzes, any suitable supportimpregnated with a solution of the composition of the invention can beused for topical application in the mouth, throat, nose or anus.Likewise, a single dose presentation (a suitable sachet or blister, forexample) of the composition of the invention can be used, which canoptionally be cooled before use so a faster and more effectivealleviation from the pain is achieved. Preferably, the liquid dosageform of the composition is ingested so that it acts on the mucosa of thewhole alimentary tract.

In any case, the skilled in the art will formulate the composition ofthe invention in any suitable presentation that allows a simple use forthe prevention and/or treatment of OTIOM. The composition of theinvention has been proved to prevent OTIOM when used daily as soon aspossible after the cancer is diagnosed and ideally at least 24h beforestarting the oncologic treatment (see Example 1). This protocol shouldbe continued along the whole duration of the cancer treatment. If thesubject already has symptoms of OTIOM, in order to prevent developing togrades 3 and 4, the composition of the invention is preferably appliedwithin the first 24 hours after onset or diagnosis of OTIOM.

The composition of the invention has been proved to treat OTIOM. Thetreatment composition should be used daily along the duration of theOTIOM episodes and at least two weeks after the cessation of signs andsymptoms (see Example 2). If radiation of rectum or prostate is given,the composition of the invention is applied locally to the anus.

A preferred administration protocol for the treatment of OTIOM is toapply the composition of the invention, with or without an applicator,while gently opening the mouth and spreading it throughout the mucosawhile swallowing the excess, so there is contact between the mucosa andthe composition not only in the mouth but also throughout the wholealimentary tract. Preferably, the composition does not comprise anysource of fluorine, this is specially preferred when the subject hassevere OTIOM.

Preferably the dosage is 2.5 to 5 ml per application, equivalent to atea spoon. Preferably, this is applied at least 3 times a day, morepreferably at least 6 and even more preferably a maximum of 10 times aday. Thus, in a preferred embodiment, the composition is administeredbetween 3 and 10 times per day.

In a preferred embodiment of the invention according to any one of thepreceding embodiments, the composition is a liquid dosage form,preferably an aqueous liquid dosage form, and more preferably an aqueoussolution or an aqueous gel. Like this, it can be easily applied in theaffected areas and even swallowed.

In a particular embodiment of the invention according to any one of theembodiments of the first aspect of the invention, the administrationprotocol is the one described in Example 1 or in Example 2.

A second aspect of the present invention refers to the use of acomposition comprising olive oil, trimethylglycine and xylitol for thepreparation of a medicament for the prevention and/or treatment ofOTIOM. The particular and preferred embodiments of the composition ofthe invention described for the first aspect of the invention areapplicable to the second aspect of the invention.

A third aspect of the present invention refers to a method of treatingOTIOM in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a composition comprisingolive oil, TMG and xylitol. The particular and preferred embodiments ofthe composition of the invention described for the first aspect of theinvention are applicable to the third aspect of the invention.

In a particular embodiment of the third aspect of the invention, themethod of treating OTIOM in a subject in need thereof, comprisesadministering to the subject a therapeutically effective amount of thecomposition of the invention as defined in any of the embodiments of thefirst aspect of the invention, said administration to the subject beingcommenced as soon as the first signs and symptoms appear. It is givendaily, at least 3 times a day, preferably at least 6 times. Preferablyit is not administered more than 10 times per day. Thus, in a particularembodiment, the composition is administered between 3 and 10 times perday, preferably between 6 and 10 times per day. In a preferredembodiment according to any one of the preceding embodiments, the dosageis 2.5 to 5 ml per application, equivalent to a tea spoon. Thecomposition is administered with or without an applicator, while gentlyopening the mouth and spreading it throughout the mucosa whileswallowing the excess.

In a preferred embodiment according to any one of the precedingembodiments of the third aspect of the invention, the composition isformulated as a liquid dosage form, more preferably as an aqueous liquiddosage form and even more preferably as an aqueous solution. In apreferred embodiment according to any one of the preceding embodiments,the composition does not comprise any fluorine source. More preferablyit comprises hydroxytyrosol, tyrosol and oleuropein. And even morepreferably, the composition is the one of formulation 5 or 6.

In a preferred embodiment, the protocol of administration of thecomposition of the invention is as described in Example 2.

Preferably, the administration of the composition of the invention isadministered along the whole duration of the cancer treatment, and morepreferably during at least two weeks more after the end of the cancertreatment.

A fourth aspect of the present invention refers to a method ofpreventing OTIOM in a subject which comprises administering to thesubject a prophylactically effective amount of a composition comprisingolive oil, TMG and xylitol. Said administration to the subject beingcommenced as soon as possible after being diagnosed with cancer andknowing when the cancer-therapy starts, and at least 24 hours beforestarting the oncologic treatment. The composition should be administeredduring the whole cancer treatment, preferably without stopping betweentherapy cycles. If the subject already has symptoms of OTIOM, in orderto prevent developing to grades 3 and 4, the composition of theinvention is preferably applied within the first 24 hours after onset ordiagnosis of OTIOM.

Preferably an aqueous liquid dosage form, more preferably an aqueoussolution, is topically applied to the oral mucosa with topicalapplication of 2.5-5ml of the composition of the invention. It isapplied daily, several times a day, starting at least 24 h before thecancer therapy regimen is started. In a preferred embodiment, theprotocol of administration is as described in Example 1, without beinglimited to the formulation therein described.

A fifth aspect of the present invention refers to a compositioncomprising olive oil, TMG and xylitol, according to any one of theembodiments of the composition of the invention described in the firstaspect of the invention. Particularly, it refers to a compositioncomprising an antioxidant selected from the group consisting ofhydroxytyrosol, tyrosol, oleuropein and mixtures thereof (i.e.hydroxytyrosol and/or tyrosol and/or oleuropein). Preferably, itcomprises hydroxytyrosol, tyrosol and oleuropein.

In another particular embodiment, the composition does not comprise asource of fluorine.

Examples of composition comprising these antioxidants and withoutfluorine sources are the formulation 5 and 6 of the present invention,which are therefore preferred embodiments of the fifth aspect of theinvention.

EXAMPLES

Specific embodiments of the invention that serve to illustrate theinvention without limiting the scope thereof are described in detailbelow.

Example 1 Study Of Prevention of Otiom

1.1.—Subjects

Fifty four patients (26 men and 28 women) aged from 12 to 95 withdifferent cancer diagnosis (Table 3) and different oncologic treatments(surgery, chemo-radiotherapy, radiotherapy or a combination of them)(Table 4) were included in the study.

TABLE 3 Cancer diagnose Total cases Test group Control group Head andneck 14 7 7 Colorectal 4 1 3 Stomach 2 2 0 Gastrointestinal carcinoid 11 0 Leukemia 5 5 0 Lymphoma 4 3 1 Breast 10 7 3 Melanoma 1 1 0Pancreatic 2 2 0 Prostate 3 2 1 Lung 8 7 1

TABLE 4 Treatment Number of patients Surgery + Chemotherapy +Radiotherapy 34 Surgery + Chemotherapy 7 Chemotherapy 10 Surgery +Radiotherapy 2 Chemotherapy + Radiotherapy 1

1.2.—Inclusion and Exclusion Criteria

Inclusion

Patients with a cancer diagnosed, who require an oncologic treatment aschemotherapy and/or radiotherapy with or without surgery. Patients witha good oral hygiene habit and with the intention of using the productsfollowing the protocol received.

Exclusion

Those patients who did not comply with the inclusion criteria wereexcluded of the study.

1.3.—Study Design

-   -   Thirty eight out of the 54 patients with a diagnosed cancer had        not started with any of the oncologic treatments before the        beginning of the study. These patients were asked to use the        test products with the defended composition at least 24 h in        advance to the oncologic treatment start up. This group of        patients was namely the test group.    -   The other 16 patients did not use the products with the        composition of the present invention. This group of patients was        namely the control group.

The protocol consisted in:

-   -   Brushing teeth with the composition (formulation 1) after main        meals.    -   Rinsing with the composition (formulation 2) before or after        brushing (patient choice).    -   Applying the composition (formulation 3) or the composition        (formulation 4) between brushings whenever the patient felt pain        or discomfort.    -   Applying the composition (formulation 5) in the oral cavity with        a small spoon at a dosage of 2.5 to 5 ml (equivalent to a tea        spoon) before and after every chemo or radiotherapy session.        Application by spreading the composition all around the oral        mucosa with the tongue, lips or by means of mild mouth movements        and swallowing the excess to allow the composition to act in the        alimentary tract.

This protocol was continued during the whole duration of the cancertreatment. The test and control group reported at the end of theoncologic treatment the onset or not of OTIOM. Whenever OTIOM appeared,patient reported the degree diagnosed by his/her oncologist as per theWHO classification.

1.4.—Used Formulations

Formulation 1: Toothpaste

Percentage Component (w/w) Olive oil 2.225 TMG 4.000 Xylitol 10.000Others: cicatrizing (0.05%), abrasive (18%), 83.775 antioxidant (0.05%),proteolytic enzyme (0.1%), remineralising (0.22%), buffer (3.2%),rheologic (1.2%), sweetener, preservative (0.1%), aroma (0.5%),essential oil (0.075%), colorant (1.0%), moisturizing (31.53%), water(27.75%).

Formulation 2: Aqueous Solution (as Mouthwash)

Percentage Component (w/w) Olive oil 0.200 TMG 2.000 Xylitol 1.000 Otheragents: emulsifier (2%), cicatrizing (0.25%), 96.800 antioxidant(0.05%), remineralising (0.07%), buffer (0.2%), preservative (0.65%),aroma (0.405%), essential oil (0.03), colorant (0.05%), moisturising(3%), water (90.095%).

Formulation 3: Aqueous Gel

Percentage Component (w/w) Olive oil 1.111 TMG 4.000 Xylitol 10.000Other agents: cicatrizing (0.05%), antioxidant 84.889 (0.05%),remineralising (1.0%), buffer (7.65%), rheological (2.5%), preservative(0.42%), essential oil (0.037%), aroma (0.5%), moisturizing (42.682%),water (30%).

Formulation 4: Aqueous Spray

Percentage Component (w/w) Olive oil 1.000 TMG 2.000 Xylitol 10.000Other agents: emulsifier (5.75%), cicatrizing 87.000 (0.7%), antioxidant(0.5%), remineralising (0.5%), buffer (0.2%), preservative (0.8%), aroma(0.405%), essential oil (0.143%), moisturising (3%), water (75.002%).

Formulation 5: Aqueous Gel

Percentage Component (w/w) Olive oil 0.500 TMG 4.000 Xylitol 10.000Other agents: rheological (1.1%), cicatrizing 85.500 (0.05%),antioxidant (0.15%), pH regulating agent (2.5%), preservative (0.42%),moisturising (34.5%), water (46.78%).

1.5.—Results

One out the 38 patients of the test group declared to not comply withthe protocol due to personal reasons. Also one out the 16 patients ofthe control group declared to have interrupted the protocol. Bothpatients were excluded from the data analysis.

The results for the 37 patients of the test group were as follows (Table5):

TABLE 5 Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 27 (72.97%) 7 (18.92%) 3(8.11%) 0 (0%) 0 (0%)

The results for the 15 patients of the control group were as follows(Table 6):

TABLE 6 Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 1 (6.67%) 2 (13.33%) 8(53.33%) 2 (13.33%) 2 (13.33%)

Differences in the number and grade of OTIOM reported from the controland test group were statistically significant (p<0.0001).

Differences in the number of patients that reported mild and moderateOTIOM (grades 1 and 2) from the test group versus the control group werestatistically significant (p<0.0409). Said difference for OTIOM of grade2 was also statistically significant (p<0.01).

Differences in the number of patients that reported severe OTIOM (grades3 and 4) from the test group versus the control group were statisticallysignificant (p<0.0409).

None of the studied patients developed gastrointestinal adverse effectsas a result of swallowing of the composition of the invention. Also, nohypersensitivity reaction to treatment was observed in any patient.

1.6.—Conclusions

Using the compositions of the present invention prevents any OTIOM (i.e.OTIOM grade 0) in 73% of cases (p<0.0001).

Using the compositions of the present invention prevents severe andlife-threatening OTIOM (Grades 3 and 4) in 100% of cases (p<0.0409).

Using the compositions of the present invention reduces the appearanceof mild and moderate OTIOM (grades 1 and 2) (p<0.0409)

Example 2 Study of Treatment of Otiom

2.1.—Subjects

Twenty patients (8 men and 12 women) aged from 45 to 88 with differentdiagnosed cancers (Table 7) and different oncologic treatments (surgery,chemo-radiotherapy, radiotherapy or a combination of them) (Table 8)were included in the study.

TABLE 7 Cancer diagnose Number of patients Head and neck 9 Colorectal 3Lymphoma 1 Breast 4 Prostate 1 Lung 1 Esophagus 1

TABLE 8 Treatment Number of patients Surgery + Chemotherapy +Radiotherapy 11 Surgery + Chemotherapy 2 Chemotherapy 5 Surgery +Radiotherapy 1 Chemotherapy + Radiotherapy 1

2.2.—Inclusion and exclusion criteria

Inclusion Criteria

Patients with diagnosed cancer, undergoing an oncologic treatment aschemotherapy and/or radiotherapy, with or without surgery, who havinghad developed mucositis in a previous cycle of treatment were noticingthe onset of mucositis in a current cycle.

Oral hygiene measures were instructed by the oncological team, varyingfrom normal oral hygiene measures to prohibition of tooth brushing.

Exclusion Criteria

Patients that were using the tested products before starting the studywere not allowed to participate.

Those patients that did not comply with the inclusion criteria wereexcluded from the study.

2.3.—Study Design

Once the oncologic team detected orogastrointestinal mucositis, patientand nurse were instructed to use of the products following the protocolconsisting in:

-   -   1. Before every chemo or radiotherapy session, applying 2.5 to 5        ml (equivalent to a tea spoon) of the composition        (formulation 5) in the oral cavity with a small spoon. Spreading        the solution all around the oral mucosa with the tongue, lips        and mild mouth movements and swallowing the excess to allow the        solution to act in the alimentary tract.    -   2. During the session days, applying the composition        (formulation 5) whenever discomfort appears, or even in absence        of discomfort applying the product at least 3 times per day.    -   3. Applying the composition (formulation 5) at least 3 times a        day during non-session days.    -   4. Applying the composition (formulation 5) before going to bed.        If patient wakes up during the night do another application.    -   5. Rinsing with the composition (formulation 6) after meals to        remove excess debris and food remnants and spit.

This protocol should be followed during the whole cycle and kept for twomore weeks after the cycle had ended and should be started as soon asthe first signs and symptoms appear. A comparison of the duration ofOTIOM between previous and current cycles was performed.

All patients were asked to fill in a short questionnaire regarding theirprospective feelings of fear with which they faced the next treatmentbased on what they had experienced in the previous cycle. The answer wasgraded as 0 (no fear), 1 (moderate fear) and 2 (high fear). Patientswere asked the same question before starting with the treatment and atthe end of the two weeks posterior to the cycle of treatment end.Results were compared (see Table 11 below).

2.4.—Formulations

Formulation 5 (as Above):

Percentage Component (w/w) Olive oil 0.500 TMG 4.000 Xylitol 10.000Other agents: rheological (1.1%), cicatrizing 85.500 (0.05%),antioxidant (0.15%), pH regulating agent (2.5%), preservative (0.42%),moisturising (34.5%), water (46.78%).

Formulation 6: Aqueous Spray

Percentage Component (w/w) Olive oil 0.200 TMG 2.000 Xylitol 1.000 Otheragents: pH regulating agent (1%), emulsifier 96.800 (2%), antioxidant(0.05%), preservative (0.65%), cicatrizing (0.05%), moisturising (2%),water (91.05%).

2.5.—Results

One of the patients informed of non-compliance with the protocol forpersonal reasons, so he was excluded from the data analysis.

The rest of patients declared an immediate improvement because theyexperienced a reduction of the symptoms and a reduction in the durationtime compared with OTIOM developed during previous cycles.

Due to the accumulative toxic effect described by many authors somepatients were experiencing a higher grade of mucositis in the currentcycle (before starting to use the composition of the invention) than inthe previous cycle (see Table 9).

TABLE 9 Comparison in the grade of mucositis between previous, beforestarting treatment with the composition, and current cycle Number ofpatients Same grade 13 One more grade 5 Two more grades 1

Comparison in the duration time with OTIOM was done between the previouscycle (without administering the composition of the invention) andcurrent cycle (administering the composition of the invention) only inthose patients who developed the same grade of mucositis in both cycles.

Differences in the duration time by grade of OTIOM developed and as awhole between previous and current cycle are included in Table 10.Differences of all the grades are statistically significant (p=0.01).

TABLE 10 Average duration time with OTIOM by grades and as a wholebetween previous treatment cycle and current cycle. Grade 4 Grade 3Grade 2 Grade 1 Whole Previous 28 21 11 5 12.46 cycle (days) Currentcycle 16 8.5 4.5 1.33 5.27 (days) % reduction 43 60 59.1 73.4 57.7

None of the studied patients developed gastrointestinal adverse effectsas a result of swallowing of the composition of the invention. Also, nohypersensitivity reaction to treatment was observed in any patient.

All patients benefited from a significant reduction in the recovery timebetween the OTIOM episode treated with the composition of the invention,and previous episodes of OTIOM not treated with said composition.

Regarding the fear patients anticipated for the next treatment theauthors of the invention included a simple question about how much fearthey felt when they faced the next cycle of treatment, as explained inthe last paragraph of section 2.3.

Fear is a major problem because an important number of patients drop thecancer treatment out of fear feeling incapable to endure the toxiceffects of a new cycle. If the patients were less fearful probably theywould be ready for the next treatment cycle and therefore fewer delaysand fewer second line treatment options would be needed. The authors ofthe invention were satisfied with the results. As shown in Table 11,patients after using the composition of the invention felt more at easewith future treatments. Differences were statistically significant(p=0.05).

TABLE 11 Average fear before current cycle Average fear after currentcycle with with composition composition 0.75 0.5

After the completion of the study, the authors of the present inventionfound a better predisposition of the majority of the patients towardsnext treatment cycle, probably based on the fact that even in the caseswhom had previously experienced nausea, mouth ulcers, vomiting,inability to eat or drink or even haemorrhagic diarrhea now felt thatthe composition of the invention would help them escape suffering any ofthese.

2.6.—Conclusions

The duration of OTIOM was reduced with the use of the composition of thepresent invention in all cases, i.e. when applied to patients with anygrade of mucositis. The differences were statistically significant(p=0.01). All patients had a more confident attitude towards futuretreatment after using the composition of the present invention.

Example 3 Comparative Study of Prevention

3.1.—Subjects

60 patients (27 men and 33 women) aged from 25 to 78 with differentcancer diagnosis and different oncologic treatments were included in thestudy.

3.2.—Inclusion and Exclusion Criteria

Inclusion

Patients with a cancer diagnosed, who require an oncological treatmentwhich has not started yet. Patients intending to follow the protocol andhaving good oral hygiene.

Exclusion

Those patients who did not comply with the inclusion criteria. Moreover,patients that were using the tested products before starting the studywere not allowed to participate.

3.3.—Study Design

Three randomized groups of 20 patients each were created.

Group 1: Composition comprising olive oil, TMG and xylitol.

Group 2: Composition comprising olive oil, but not including TMG norxylitol.

Group 3: Composition comprising xylitol and TMG, but not including oliveoil.

The protocol consisted of:

-   -   Brushing teeth with the assigned composition after meals.    -   Applying the assigned composition between brushings whenever the        patient felt pain or discomfort.    -   Applying the assigned composition before and after every chemo        or radiotherapy session.

This protocol was continued during the whole cancer treatment.

The three groups reported at the end of the oncological treatment theonset and the grade of OTIOM.

3.4.—Formulations

GROUP 1 Percentage Component (w/w) Olive oil 0.50 TMG 4.00 Xylitol 10.00Other agents: rheological (1.1%), cicatrizing (0.05%), 85.50 antioxidant(0.15%), pH regulating agent (2.5%), preservative (0.42%), moisturising(34.5%), water (46.78%).

GROUP 2 Percentage Component (w/w) Olive oil 0.50 TMG 0.00 Xylitol 0.00Other agents: rheological (1.1%), cicatrizing (0.05%), 99.50 antioxidant(0.15%), pH regulating agent (2.5%), preservative (0.42%), moisturising(34.5%), water (60.78%).

GROUP 3 Percentage Component (w/w) Olive oil 0.00 TMG 4.00 Xylitol 10.00Other agents: rheological (1.1%), cicatrizing (0.05%), 86.00 antioxidant(0.15%), pH regulating agent (2.5%), preservative (0.42%), moisturising(34.5%), water (47.28%).

3.5.—Results and Conclusions

The results of Groups 1, 2 and 3 are shown in Table 12.

TABLE 12 Treatment Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 GROUP 1 15(75%)  5 (25%) 0 (0%)  0 (0%)  0 (0%) GROUP 2 3 (15%) 5 (25%) 7 (35%) 4(20%) 1 (5%) GROUP 3 4 (20%) 7 (35%) 2 (10%) 5 (25%)  2 (10%)

Group 1, using the composition of the invention (comprising olive oil,xylitol and TMG), did not develop OTIOM, measured as grade 0, in 75% ofcases. In contrast, Group 2, using the composition with only olive oil,has 15% of patients with grade 0, and Group 3, using the compositionwith xylitol and TMG, shows 20% of patients with grade 0. That is, only15% and 20% of the patient of Groups 2 and 3, respectively, did notdevelop OTIOM.

Furthermore, using the composition of the invention (Group 1) preventssevere and life-threatening OTIOM (grades 3 and 4) in 100% of cases,showing a statistically significant difference with the other two groups(p=0.01 with the Group 2, and p=0.03) with the Group 3). In contrast, inGroups 2 and 3, 25% and 35% of the cases, respectively, present severeand life-threatening OTIOM (grades 3 and 4).

Example 4 Comparative Study of Treatment

4.1.—Subjects

Sixty patients (37 women and 23 men) aged from 28 to 89 with differentdiagnosed cancers and different oncological treatments were included inthe study.

4.2.—Inclusion and Exclusion Criteria

Inclusion

Patients with diagnosed cancer, undergoing an oncological treatment aschemo and/or radiotherapy, who developed mucositis in a previous cycleof treatment and were noticing the onset of mucositis in a currentcycle.

Exclusion

Patients that were using the tested products before starting the studywere not allowed to participate.

Patients that did not comply with the inclusion criteria were excludedfrom the study.

4.3.—Study Design

Three randomized groups of 20 patients each were created.

Group 1: Composition comprising olive oil, TMG and xylitol.

Group 2: Composition comprising olive oil, but not including TMG norxylitol.

Group 3: Composition comprising xylitol and TMG, but not olive oil.

The protocol consisted of:

-   -   Brushing teeth with the assigned composition after meals.    -   Applying the assigned composition between brushings whenever the        patient felt pain or discomfort.    -   Applying the assigned composition before and after every chemo        or radiotherapy session.

This protocol was started as soon as the first signs and symptomsappeared and was followed during the whole cycle and kept for two moreweeks after the cycle had ended. Comparison of the duration of OTIOMbetween previous and current cycles was performed.

4.4.—Formulations

GROUP 1 Percentage Component (w/w) Olive oil 0.50 TMG 4.00 Xylitol 10.00Other agents: rheological (1.1%), cicatrizing (0.05%), 85.50 antioxidant(0.15%), pH regulating agent (2.5%), preservative (0.42%), moisturising(34.5%), water (46.78%).

GROUP 2 Percentage Component (w/w) Olive oil 0.50 TMG 0.00 Xylitol 0.00Other agents: rheological (1.1%), cicatrizing (0.05%), 99.50 antioxidant(0.15%), pH regulating agent (2.5%), preservative (0.42%), moisturising(34.5%), water (60.78%).

GROUP 3 Percentage Component (w/w) Olive oil 0.00 TMG 4.00 Xylitol 10.00Other agents: rheological (1.1%), cicatrizing (0.05%), 86.00 antioxidant(0.15%), pH regulating agent (2.5%), preservative (0.42%), moisturising(34.5%), water (47.28%).

4.5.—Results

The effectiveness of the treatment can be measured by comparing thegrade of mucositis of the current cycle with the grade of the previouscycle.

Due to the accumulative toxic effect, described by many authors,patients experience higher grade of mucositis in posterior cycles thanin the previous cycles. Hence, a treatment success is when patientsexperience the same grade that in the previous cycle.

TABLE 13 Comparison in the grade of mucositis between previous, beforestarting treatment with the composition, and current cycle GROUP 1 GROUP2 GROUP 3 Same grade 15 4 7 One more grade 5 13 10 Two more grades 0 3 3

As shown in Table 13, 75% of patients in Group 1 experienced the samegrade of mucositis than in the previous cycle (i.e. successfultreatment), while only 20% of Group 2 and 35% of Group 3 had the samegrade than in the previous cycle.

Differences between Group 1 and Group 2 were statistically significant(p<0.01) as well as the differences between Group 1 and Group 3(p<0.01). No differences were seen between Groups 2 and 3.

Example 5

Study of Treatment of Proctitis

5.1.—Objective, Subjects and Formulations

Proctitis, OTIOM affecting the rectum, is one late side effect of cancertreatment toxicity of the mucosa, not only in the rectum cancerpatients, but most commonly in the prostate cancer being it the mostfrequent complication when radiotherapy is applied in high doses in theabdominal pelvic area. Radiation proctitis appears at any time afterradiation of the pelvic area as a dose dependent toxic effect of theradiotherapy of cancer in the urological and gynecological or digestiveapparatus and can affect 5-20% of this group of patients. Toxicity ofrectal mucosa as a late side effect of chemotherapy has also beenreported in the form of tenesmus and diarrhea followed by episodes ofconstipation.

Bleeding, in the most severe form of proctitis, may need ferrum intakeand call in for differential diagnosis with cancer relapse or newcancerous disease.

While in the more aggressive presentation bleeding can lead to anemiaand hence transfusions, it is generally receding after some time ofclinical symptoms.

Diarrhea is accompanied with either mucous discharge or/and abdominaldiscomfort.

The objective of the study was to compare the clinical efficacy of acomposition comprising xylitol, olive oil and TMG (i.e. compositionaccording to the invention) with a placebo composition without any ofthe mentioned active ingredients in patients with proctitis afterprostate cancer treatment.

To carry out the study, 20 patients were included in the study, andrandomly divided into 2 groups. Two different compositions were tested:

Composition A (invention), comprising 0.5% Olive oil, 4.0% TMG and 10%Xylitol.

Composition B (placebo), comprising the same excipients that compositionA, but with none of the active ingredients.

5.2.—Inclusion and Exclusion Criteria

Inclusion

Patients diagnosed with proctitis due to oncological treatment, andreferring rectal discomfort/pain and rectal tenesmus were included inthe study.

Exclusion

Those patients who did not comply with the inclusion criteria wereexcluded from the study.

5.3.—Study Design

The study was crossover so everyman used both compositions randomlyassigned.

Between the administration of one composition and the next one, therewas one week of washout.

Products were packaged in white tubes identified with the number ofpatient. Content was kept in a closed envelope and only opened for datatreatment.

Every complaint was assessed by a VAS (Visual analogue scale) 100 mmlong.

VAS values reporting rectal discomfort/pain and rectal tenesmus wereobtained for every patient at four different days:

-   -   Day 0: at the beginning of the study.    -   Day 8: after first treatment period.    -   Day 15: after washout period.    -   Day 22: after second treatment period.

In all cases the products were applied rectally as a fluid gel with anapplicator dosing 5 ml. Patients applied 5 ml before going to bed everynight during the whole week.

5.4.—Results and Conclusions

In the study there were two groups but at the time of expressingresults, the groups were not taken into account. The results of the 20patients are shown in Table 14 and 15.

Rectal Discomfort/Pain

The average results obtained after using the invention or the placebocompositions are shown in Table 14.

TABLE 14 COMPOSITION INVENTION PLACEBO Average ± s.d. 29.7 53.55 p<0.000

Rectal Tenesmus

The average results obtained after using the invention or placebocompositions are shown in Table 15:

TABLE 15 COMPOSITION INVENTION PLACEBO Average 43.44 55.77 p 0.003

As shown in Tables 14 and 15, the composition according to theinvention, significantly reduces rectal discomfort/pain (p<0.000) andrectal tenesmus (p=0.003) in comparison with the placebo composition, ina group of 20 men when applied rectally once a day for a week.

Example 6 Comparative Study of Treatment of Proctitis

6.1.—Objective, Subjects and Formulations

The objective of the study was to compare the clinical efficacy of acomposition comprising including xylitol, olive oil and TMG as activeingredients, with a composition comprising only olive oil as activeingredient, in patients with proctitis after prostate cancer treatment.

For the purpose of the study 9 patients were accepted into the study.Patients were randomly divided into 2 groups (one group with 4 patientsand another one with 5 patients).

Two different compositions were tested.

Composition A (invention), comprising 0.5% Olive oil, 4.0% TMG and 10%Xylitol.

Composition B (olive oil), comprising 0.5% Olive oil, without TMG andXylitol.

6.2.—Inclusion and Exclusion criteria

Inclusion Criteria

Patients diagnosed with proctitis due to oncological treatment sufferingrectal discomfort/pain and rectal tenesmus were included in the study.

Exclusion Criteria

Those patients who did not comply with the inclusion criteria wereexcluded from the study.

6.3.—Study Design

The study design was such that everyman used both compositions randomlyassigned and used both compositions subsequently in a crossover designwith a washout period of 7 days between one and the other.

Products were packaged in white tubes identified with the number ofpatient. Content was kept in a closed envelope and only opened for datatreatment.

Every complaint was assessed by a VAS (Visual analogue scale) 100 mmlong.

VAS values resulted from rectal discomfort/pain and rectal tenesmus wereobtained for every patient at four different days:

-   -   Day 0: at the beginning of the study.    -   Day 8: after first treatment period.    -   Day 15: after washout period.    -   Day 22: after second treatment period.

In all cases the product was applied rectally as a fluid gel with anapplicator dosing 5 ml. Patients applied 5 ml before going to bed everynight during the whole week.

6.4.—Results and conclusions

In the study there were two groups but at the time of expressingresults, the groups were not taken into account.

Rectal Discomfort/Pain

The average results after using the invention or olive oil compositionsare shown in Table 16:

TABLE 16 INVENTION OLIVE OIL Average 32.44 65.55 p <0.000

Rectal Tenesmus

The average results obtained after using the invention or olive oilcompositions are shown in Table 17:

TABLE 17 INVENTION OLIVE OIL Average 37.44 62.11 p <0.000

As shown in Tables 16 and 17, the composition of the invention,significantly reduces rectal discomfort/pain (p<0.000) and rectaltenesmus (p<0.000) in comparison with the composition comprising only0.5% Olive oil as active ingredient, in a group of 9 men when appliedrectally once a day for a week.

1. Composition comprising olive oil, trimethylglycine and xylitol foruse in the prevention and/or treatment of Oncologic Treatment InducedOrogastrointestinal Mucositis.
 2. Composition for use according to claim1, wherein the composition comprises 0.1%-5% by weight of olive oil,preferably 0.2%-4% and more preferably 0.2%-2.5%.
 3. Composition for useaccording to claim 1 or 2, wherein the composition comprises 0.1%-10% byweight of trimethylglicine, preferably 1.5%-6% and more preferably2%-4%.
 4. Composition for use according to any one of claims 1-3,wherein the composition comprises 1%-50% by weight of xylitol,preferably 1%-30% and more preferably 1%-15%.
 5. Composition for useaccording to any one of claims 1-4, wherein the composition comprises anantioxidant, preferably selected from the group consisting ofhydroxytyrosol, tyrosol, oleuropein and mixtures thereof, preferably,hydroxytyrosol, tyrosol and oleuropein.
 6. Composition for use accordingto any one of claims 1-5, wherein the composition does not comprise anyfluorine source.
 7. Composition for use according to any one of claims1-6, wherein the composition is in a liquid dosage form, preferably anaqueous liquid dosage form.
 8. Composition for use according to any oneof claims 1-7, wherein the composition further comprises an additionalcomponent selected from the group consisting of: remineralising agents,viscosity-controlling agents, moisturising agents, preservatives,colorants, pH-regulating agents, sweeteners, proteolytic enzymes,emulsifiers, abrasives, essential oils, cicatrizing agents, aromas,antioxidants, animal or plant gelatines, excipients, and mixturesthereof.
 9. Composition for use according to claim 8, wherein thecomposition comprises a cicatrizing agent, an antioxidant agent, abuffer, a preservative, a moisturizing agent and a solvent; andoptionally a rheological agent and/or an emulsifier.
 10. Composition foruse according to claim 8 or 9, comprising a sweetener, a colorant, anaroma, an essential oil, an abrasive agent, a proteolytic enzyme, aremineralising or combinations thereof.
 11. Composition for useaccording to claim 8 or 9, wherein the composition does not comprise anyof aroma, essential oil, abrasive agent, proteolytic enzyme and fluorinesource.
 12. Composition for use according to claim 11, wherein thecomposition is for use in the treatment of Oncologic Treatment InducedOrogastrointestinal Mucositis, preferably of severe grade. 13.Composition for use according to any one of claims 1-11, wherein thecomposition is for use in the prevention of Oncologic Treatment InducedOrogastrointestinal Mucositis, and it is administered before and aftereach oncologic treatment.
 14. Composition for use according to any oneof claims 1-13, wherein the composition does not comprise any additionalactive principle.
 15. Composition for use according to any one of claims1-14, wherein OTIOM affects the oral cavity, tongue, lips, pharynx,esophagus, stomach, intestine, rectum, anus, nose, nasal tract,paranasal sinuses, throat, vocal cords, larynx, and combinationsthereof.
 16. Composition comprising: olive oil, trimethylglycine,xylitol, and hydroxytyrosol and/or tyrosol and/or oleuropein, preferablyhydroxytyrosol, tyrosol and oleuropein.
 17. Composition according toclaim 16, wherein the composition does not comprise any source offluorine.